Crystal structure of the Na+/H+ antiporter NhaA at active pH reveals the mechanistic basis for pH sensing

Iven Winkelmann, Povilas Uzdavinys, Ian M. Kenney, Joseph Brock, Pascal F. Meier, Lina-Marie Wagner, Florian Gabriel, Sukkyeong Jung, Rei Matsuoka, Christoph Ballmoos, Oliver Beckstein () and David Drew ()
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Iven Winkelmann: Stockholm University
Povilas Uzdavinys: Stockholm University
Ian M. Kenney: Arizona State University
Joseph Brock: Stockholm University
Pascal F. Meier: Stockholm University
Lina-Marie Wagner: Stockholm University
Florian Gabriel: Stockholm University
Sukkyeong Jung: Stockholm University
Rei Matsuoka: Stockholm University
Christoph Ballmoos: University of Bern
Oliver Beckstein: Arizona State University
David Drew: Stockholm University

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract The strict exchange of protons for sodium ions across cell membranes by Na+/H+ exchangers is a fundamental mechanism for cell homeostasis. At active pH, Na+/H+ exchange can be modelled as competition between H+ and Na+ to an ion-binding site, harbouring either one or two aspartic-acid residues. Nevertheless, extensive analysis on the model Na+/H+ antiporter NhaA from Escherichia coli, has shown that residues on the cytoplasmic surface, termed the pH sensor, shifts the pH at which NhaA becomes active. It was unclear how to incorporate the pH senor model into an alternating-access mechanism based on the NhaA structure at inactive pH 4. Here, we report the crystal structure of NhaA at active pH 6.5, and to an improved resolution of 2.2 Å. We show that at pH 6.5, residues in the pH sensor rearrange to form new salt-bridge interactions involving key histidine residues that widen the inward-facing cavity. What we now refer to as a pH gate, triggers a conformational change that enables water and Na+ to access the ion-binding site, as supported by molecular dynamics (MD) simulations. Our work highlights a unique, channel-like switch prior to substrate translocation in a secondary-active transporter.

Date: 2022
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DOI: 10.1038/s41467-022-34120-z

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